EP4112723B1 - Lignée cellulaire d'hybridome de carbapénémase de type anti-kpc, anticorps monoclonal et son application - Google Patents

Lignée cellulaire d'hybridome de carbapénémase de type anti-kpc, anticorps monoclonal et son application Download PDF

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Publication number
EP4112723B1
EP4112723B1 EP21870568.9A EP21870568A EP4112723B1 EP 4112723 B1 EP4112723 B1 EP 4112723B1 EP 21870568 A EP21870568 A EP 21870568A EP 4112723 B1 EP4112723 B1 EP 4112723B1
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Prior art keywords
seq
antibody
variable region
chain variable
kpc
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German (de)
English (en)
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EP4112723A4 (fr
EP4112723A1 (fr
EP4112723C0 (fr
Inventor
Xing Wang
Yongsheng He
Qinghua Yuan
Yuehui Zhou
Yufang Wang
Danrong ZANG
Yamiao WANG
Shilin LI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beihai Sinlon Biotech Co Ltd
Tianjin Era Biology Techology Co Ltd
Beijing Gold Mountainriver Tech Development Co Ltd
Era Biology Suzhou Co Ltd
Original Assignee
Beihai Sinlon Biotech Co Ltd
Tianjin Era Biology Techology Co Ltd
Beijing Gold Mountainriver Tech Development Co Ltd
Era Biology Suzhou Co Ltd
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Publication of EP4112723A4 publication Critical patent/EP4112723A4/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1203—Gram-negative bacteria
    • C07K16/1228—Enterobacterales (O), e.g. Citrobacter (G), Serratia (G), Proteus (G), Providencia (G), Morganella (G) or Yersinia (G)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/978—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • G01N2333/986—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in cyclic amides (3.5.2), e.g. beta-lactamase (penicillinase, 3.5.2.6), creatinine amidohydrolase (creatininase, EC 3.5.2.10), N-methylhydantoinase (3.5.2.6)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis

Definitions

  • Carbapenems are one of the most effective drugs for controlling clinical pathogen infections.
  • CPOs Carbapenemase-producing organisms
  • CRE carbapenem-resistant Enterobacteriaceae
  • Enterobacteriaceae bacteria are important pathogens causing nosocomial infection and community-acquired infection.
  • cephalosporins due to the wide application of cephalosporins, a proportion of strains producing extended spectrum beta-lactamases (ESBLs) and AmpC enzymes in Enterobacteriaceae has been on the rise significantly, and carbapenem antibacterial drugs are the drugs of choice for treating infections of such strains.
  • EP 3 230 741 A1 discloses mAbs binding KPC-carbapenemase and their use for detecting carbapenemase.
  • WO 2013/112696 A1 discloses pharmaceutical compositions having anti-serine carbapenemase antibodies having antibacterial anti-KPC activity which are capable of killing KPC-expressing strains. It does not disclose any information about the capability of the antibody to detect the antigen nor about the lower limit of detection of the presence of the antigen by using the antibody
  • the present disclosure provides an anti-KPC-type carbapenemase hybridoma cell line, and a mAb and use thereof.
  • the light chain variable region has an amino acid sequence shown in SEQ ID NO: 7
  • the heavy chain variable region may have an amino acid sequence shown in SEQ ID NO: 9
  • a nucleic acid including nucleotides encoding the anti-KPC-type carbapenemase antibody described above.
  • the present disclosure also relates to a KPC-type carbapenemase-resistant hybridoma cell line named HD6.
  • the KPC-type carbapenemase-resistant hybridoma cell line capable of stably secreting an anti-KPC-type carbapenemase antibody and a variable region sequence thereof provided by the present disclosure are obtained through mouse hybridoma mAb screening and reverse transcription-polymerase chain reaction (RT-PCR) to clone an Ig variable region gene, and the binding specificity of the antibody is identified by ELISA.
  • RT-PCR reverse transcription-polymerase chain reaction
  • the light chain variable region may have an amino acid sequence shown in SEQ ID NO: 7
  • the heavy chain variable region may have an amino acid sequence shown in SEQ ID NO: 9;
  • An antibody 1HD6 produced by the KPC-type carbapenemase-resistant hybridoma cell line includes a light chain variable region and a heavy chain variable region, where the light chain variable region includes CDR1 shown in SEQ ID NO: 11, CDR2 shown in SEQ ID NO: 12, and CDR3 shown in SEQ ID NO: 13; and
  • the anti-KPC-type carbapenemase antibodies produced by the hybridoma cell line 1HG11 and the hybridoma cell line 1HD6 can be used to detect a KPC-type carbapenemase antigen.
  • the anti-KPC-type carbapenemase mAb shows prominent performance in all aspects, and thus is suitable as an immunodiagnostic reagent for the preparation of an in vitro diagnostic kit, and the in vitro diagnostic kit may be a colloidal gold immunoassay kit, a chemiluminescence kit, a radioimmunoassay kit, an ELISA kit, or a fluoroimmunoassay kit.
  • the anti-KPC-type carbapenemase antibody can be made into a microfluidic chip for detecting a KPC-type carbapenemase antigen.
  • a KPC-type carbapenemase antigen first needs to be extracted to obtain a high-purity antigen, the antigen is used to stimulate an excellent immune response in mice, and then the hybridoma technique is used to screen an antibody with high affinity and specificity for the development of related in vitro diagnostic reagents.
  • the two antibodies involved in this solution are especially suitable for preparing an immune colloidal gold test strip of a double-antibody sandwich method, where the antibody 1HG11 is used as a coating antibody and the antibody 1HD6 is used as a gold-labeled antibody.
  • the prepared immune colloidal gold test strip of a double-antibody sandwich method is more sensitive.
  • the antibody 1HG11 can be used as a gold-labeled antibody
  • the antibody 1HD6 can be used as a coating antibody.
  • the present disclosure is further described below through specific examples. Experimental methods for which operation steps are not specified are all conducted in accordance with the corresponding product instructions. The instruments, reagents, and consumables used in the examples can be purchased from commercial companies unless otherwise specified.
  • a KPC-type gene sequence was searched and downloaded from National Center for Biotechnology Information (NCBI), subjected to gene synthesis, and ligated to a pet-28a vector, and then the vector plasmid pet-28a-KPC carrying the target gene was transformed into an expression host Rosseta (DE3).
  • the host was cultivated until an OD value of a bacterial solution was of 0.4 to 0.6, then isopropylthio- ⁇ -galactoside (IPTG) was added at a final concentration of 1 mM for induction, and the host was further cultivated at 37°C for 3 hours.
  • Resulting bacterial cells were collected by centrifugation, then resuspended by adding 30 mL of phosphate buffered saline (PBS) to every about 1 g of the bacterial cells, and then subjected to ultrasonication at a power of 400 W for about 30 min (ultrasonic time: 3 s, interval: 5 s); and after a bacterial solution was non-viscous and clear, the bacterial solution was centrifuged to remove bacterial debris, and a resulting supernatant was filtered through a 0.45 ⁇ m filter membrane and loaded on a nickel column packed and equilibrated with an equilibration buffer in advance.
  • PBS phosphate buffered saline
  • mice For an initial immunization, an appropriate amount of the KPC-type carbapenemase was taken and diluted with distilled water to 300 ⁇ L, then 300 ⁇ L of complete Freund's adjuvant (CFA) was added for thorough emulsification, and a resulting emulsion was subcutaneously injected into the mice (multi-point injection); two weeks later, the mice were subjected to a secondary immunization by intraperitoneal injection at the same dosage; two weeks later, the mice were subjected to an additional immunization by intraperitoneal injection; 7 days later, blood was collected from the tail of mice, and a serum titer of the mice was determined by ELISA.
  • CFA complete Freund's adjuvant

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • Biophysics (AREA)
  • Food Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Claims (6)

  1. Anticorps anti-carbapénémase de type KPC, dans lequel l'anticorps anti-carbapénémase de type KPC est : un anticorps 1HG11 comprenant une région variable de chaîne légère et une région variable de chaîne lourde, dans lequel la région variable de chaîne légère comprend la région de détermination complémentaire 1 (CDR1) représentée dans SEQ ID NO : 1, CDR2 représentée dans SEQ ID NO : 2, et CDR3 représentée dans SEQ ID NO : 3 ; et la région variable de chaîne lourde comprend la CDR1 représentée dans SEQ ID NO : 4, CDR2 représentée dans SEQ ID NO : 5, et CDR3 représentée dans SEQ ID NO : 6, la région variable de chaîne légère a une séquence d'acides aminés représentée dans SEQ ID NO : 7, et la région variable de chaîne lourde a une séquence d'acides aminés représentée dans SEQ ID NO : 9 ;
    ou,
    un anticorps 1HD6 comprenant une région variable de chaîne légère et une région variable de chaîne lourde, dans lequel la région variable de chaîne légère comprend CDR1 représentée dans SEQ ID NO : 11, CDR2 représentée dans SEQ ID NO : 12, et CDR3 représentée dans SEQ ID NO : 13 ; et la région variable de chaîne lourde comprend la CDR1 représentée dans SEQ ID NO : 14, CDR2 représentée dans SEQ ID NO : 15, et CDR3 représentée dans SEQ ID NO : 16, la région variable de chaîne légère a une séquence d'acides aminés représentée dans SEQ ID NO : 17, et la région variable de chaîne lourde a une séquence d'acides aminés représentée dans SEQ ID NO : 19.
  2. Acide nucléique, comprenant des nucléotides codant pour l'anticorps anti-carbapénémase de type KPC selon la revendication 1.
  3. Acide nucléique selon la revendication 2, dans lequel une séquence nucléotidique de l'acide nucléique pour coder la région variable de chaîne légère de l'anticorps 1HG11 est représentée dans SEQ ID NO : 8, et une séquence nucléotidique de l'acide nucléique pour coder la région variable de chaîne lourde de l'anticorps 1HG11 est représentée dans SEQ ID NO : 10 ;
    ou,
    une séquence nucléotidique de l'acide nucléique pour coder la région variable de chaîne légère de l'anticorps 1HD6 est représentée dans SEQ ID NO : 18, et une séquence nucléotidique de l'acide nucléique pour coder la région variable de chaîne lourde de l'anticorps 1HD6 est représentée dans SEQ ID NO : 20.
  4. Utilisation de l'anticorps anti-carbapénémase de type KPC selon la revendication 1 dans la préparation d'un réactif pour détecter un antigène de carbapénémase de type KPC.
  5. Utilisation de l'anticorps anti-carbapénémase de type KPC dans la préparation d'un réactif pour détecter un antigène de carbapénémase de type KPC selon la revendication 4, dans lequel l'anticorps anti-carbapénémase de type KPC est utilisé dans un kit de diagnostic in vitro ou une puce microfluidique ; et le kit de diagnostic in vitro est un kit de dosage immunologique d'or colloïdal, un kit de chimioluminescence, un kit de dosage radio-immunologique, un kit de dosage d'immunoabsorption enzymatique (ELISA), ou un kit de dosage immunologique au fluor.
  6. Utilisation de l'anticorps anti-carbapénémase de type KPC dans la préparation d'un réactif pour détecter un antigène de carbapénémase de type KPC selon la revendication 4, dans lequel une bande de test d'or colloïdal immunitaire d'un procédé sandwich à double anticorps est préparée, dans lequel l'anticorps 1HG11 est utilisé en tant qu'anticorps de revêtement et l'anticorps 1HD6 est utilisé en tant qu'anticorps marqué à l'or ; ou
    l'anticorps 1HD6 est utilisé en tant qu'anticorps de revêtement et l'anticorps 1HG11 est utilisé en tant qu'anticorps marqué à l'or.
EP21870568.9A 2021-05-12 2021-12-03 Lignée cellulaire d'hybridome de carbapénémase de type anti-kpc, anticorps monoclonal et son application Active EP4112723B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110514080.2A CN112980804B (zh) 2021-05-12 2021-05-12 一种抗kpc型碳青霉烯酶杂交瘤细胞株，单克隆抗体及应用
PCT/CN2021/135406 WO2022237138A1 (fr) 2021-05-12 2021-12-03 Lignée cellulaire d'hybridome de carbapénémase de type anti-kpc, anticorps monoclonal et son application

Publications (4)

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EP4112723A1 EP4112723A1 (fr) 2023-01-04
EP4112723A4 EP4112723A4 (fr) 2023-03-08
EP4112723B1 true EP4112723B1 (fr) 2024-07-03
EP4112723C0 EP4112723C0 (fr) 2024-07-03

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EP (1) EP4112723B1 (fr)
CN (1) CN112980804B (fr)
WO (1) WO2022237138A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112500489B (zh) * 2021-02-07 2021-05-04 天津一瑞生物科技股份有限公司 一种抗oxa-23型碳青霉烯酶杂交瘤细胞株，单克隆抗体及应用
CN112980804B (zh) * 2021-05-12 2021-09-10 天津一瑞生物科技股份有限公司 一种抗kpc型碳青霉烯酶杂交瘤细胞株，单克隆抗体及应用
CN114317454B (zh) * 2022-03-01 2023-10-03 天津一瑞生物科技股份有限公司 一种鼠抗oxa-48型碳青霉烯酶杂交瘤细胞株，单克隆抗体及应用
CN114755420B (zh) * 2022-05-30 2023-02-03 广东聚诚生物技术有限公司 碳青霉烯酶联合检测试剂盒
CN115947856B (zh) * 2022-09-27 2026-01-30 丹娜(天津)生物科技股份有限公司 与kpc酶结合的抗体或其抗原结合片段及其应用
CN119613557B (zh) * 2024-12-20 2025-07-29 江苏美克医学技术有限公司 一种可检测多亚型kpc的抗体制备及其试剂盒的应用
CN120699158B (zh) * 2025-08-15 2025-11-11 南昌大学第一附属医院 一种抗KPC-2型碳青霉烯酶纳米抗体Nb-KPC-2及其应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9169477B2 (en) * 2012-01-27 2015-10-27 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Compositions and methods for immunization against bacteria expressing a carbapenemase
GB201503387D0 (en) * 2015-02-27 2015-04-15 ALERE TECHNOLOGIES GmbH Anti-carbapenem antibodies and uses thereof
ES2843954T3 (es) * 2015-04-10 2021-07-21 Coris Bioconcept Sprl Método y dispositivo para detectar enterobacterias productoras de carbapenemasa
CN112501131B (zh) * 2021-02-07 2021-05-04 天津一瑞生物科技股份有限公司 抗imp型碳青霉烯酶杂交瘤细胞株，单克隆抗体及应用
CN112500489B (zh) * 2021-02-07 2021-05-04 天津一瑞生物科技股份有限公司 一种抗oxa-23型碳青霉烯酶杂交瘤细胞株，单克隆抗体及应用
CN112980804B (zh) * 2021-05-12 2021-09-10 天津一瑞生物科技股份有限公司 一种抗kpc型碳青霉烯酶杂交瘤细胞株，单克隆抗体及应用

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Publication number Publication date
CN112980804A (zh) 2021-06-18
CN112980804B (zh) 2021-09-10
EP4112723A4 (fr) 2023-03-08
EP4112723A1 (fr) 2023-01-04
EP4112723C0 (fr) 2024-07-03
WO2022237138A1 (fr) 2022-11-17

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